The relationship between EVI5 and MS
Ecotropic Viral Integration Site 5 (EVI5) is a critical checkpoint in the retroviral integration process and is closely associated with various physiological processes, including the cell cycle. It plays a significant role in essential biological activities such as cell growth, division, and differentiation. In the context of MS, the proliferation and differentiation of neural stem cells and neural precursor cells may be disrupted. Mutations in the EVI5 gene can impair the normal cell cycle processes of these cells, potentially influencing the pathogenesis of MS. By regulating the expression of lymphocyte-specific factors, EVI5 has been shown to be crucial in T cell differentiation, particularly in the high expression of TH1 and TH2 cells31. The deletion of EVI5 adversely affects the differentiation of helper T cells, especially TH17 cells, leading to a significant decrease in IL-17 A production. Moreover, EVI5 also impacts genes such as HLA-DRB, CLEC16A, CD58, and IL7R, which may be linked to the immunomodulatory effects in MS32. Therefore, EVI5 may influence the pathogenesis of MS by modulating T cell differentiation and function. As a GTPase-activating protein (GAP) of Rab11, EVI5 activates the GTPase activity of Rab11, potentially participating in the regulation of the downstream RAB11 pathway33. This pathway is vital for the formation of immune synapses and T cell function. EVI5 interacts with GTP-Rab11 through its TBC domain, promoting the conversion of GTP to GDP, thereby inactivating Rab11. This regulatory mechanism may affect immune synapse formation and T cell functionality, subsequently influencing the immune response in MS. Additionally, EVI5 is involved in lipid metabolism-related pathways, which may further impact the pathological processes associated with MS34. As a member of the protein family containing the Tre-2/Bub2/Cdc16 (TBC) domain, EVI5 plays a regulatory role in the cell cycle, cell division, and cell membrane transport.The function of EVI5 may be linked to its regulatory role in cell membrane transport, which could indirectly influence lipid metabolism and inflammatory responses in MS. Additionally, EVI5 protein is closely associated with endocytosis and cell signaling. Research indicates that EVI5 may impact myelin repair by modulating the function of oligodendrocytes, the cells responsible for the formation and maintenance of myelin sheaths33. Variations in EVI5 activity can affect the survival, proliferation, and differentiation of these cells, thereby facilitating myelin regeneration. Furthermore, EVI5 may regulate immune responses by influencing cell signaling pathways. In MS, the immune system’s attack on the myelin sheath is a critical factor in initiating pathological changes. The regulatory effects of EVI5 help control immune cell activity, mitigate damage to the myelin sheath, and create favorable conditions for myelin repair35. Moreover, EVI5 may participate in the neuroinflammatory process by regulating the function of nerve cells. Neuroinflammation is a significant characteristic of MS, which can lead to myelin damage and neurodegeneration. EVI5 contributes to this process by affecting the recycling of endosomes and signaling pathways36. In summary, EVI5 is intricately linked to the onset and progression of MS and represents a crucial gene in the pathogenesis of the disease.
The potential therapeutic application of the EVI5 gene in MS shows considerable promise. Research has demonstrated that variations in the EVI5 gene are significantly associated with the risk of developing MS37. These variations may influence the function of the EVI5 protein and, consequently, play a role in the pathophysiological processes underlying MS38. Furthermore, variations in EVI5 may not only act as risk factors for MS but also serve as potential biomarkers for early diagnosis and prognostic assessment of the disease. By regulating the expression of EVI5, the activation of T cells and B cells, as well as their roles in MS, can be modulated, potentially improving patient symptoms38. These characteristics position EVI5 as a promising target for MS treatment, providing both a theoretical foundation and the possibility for the development of novel therapeutic strategies.
Sanguinarine is an alkaloid extracted from the bloodroot plant, which belongs to the poppy family. It exhibits a high binding energy with EVI5. Recent research has revealed its multifaceted effects on the immune system, demonstrating its ability to modulate the host’s immune response through various mechanisms. Sanguinarine shows potential in enhancing immune function and combating certain immune-related diseases. It can bolster the body’s defense against pathogens by adjusting the composition and diversity of intestinal flora, which may enhance the host’s immune response through the regulation of the intestinal microbiome39. Furthermore, sanguinarine plays a significant role in strengthening the body’s innate immune response by regulating reactive oxygen species (ROS) and activating the PMK-1/SKN-1 signaling pathway39. This mechanism has shown promising effects across different organisms, including improvements in the body’s resistance to oxidative stress. At the level of immune cells, sanguinarine influences the production of inflammatory cytokines by modulating multiple signaling pathways, such as MAPK, Wnt/β-catenin, NF-κB, JAK/STAT, TGF-β, and PI3K/Akt/mTOR pathways40. These interactions indicate that sanguinarine has dual effects on inflammatory and immune responses. Given its complex effects on the immune system and chronic inflammation, sanguinarine holds promise for applications in the treatment of immune-related diseases, chronic inflammation, and allergic reactions.
The relationship between TNFRSF14 and MS
TNFRSF14, a member of the tumor necrosis factor receptor superfamily 14 and also known as HVEM, is a protein that plays a crucial role in the immune response. It is significant in regulating lymphocyte activation and proliferation. Studies have demonstrated that HVEM can effectively modulate the immune response of T cells by activating the inflammatory response and transmitting inhibitory signals41,42. HVEM not only serves as a receptor for LIGHT and lymphotoxin-alpha but also interacts with immunoglobulin superfamily members BTLA and CD160. This versatility positions HVEM uniquely within the realm of immunomodulation. It is capable of binding to multiple ligands in various conformations, thereby forming complex and interconnected signaling networks that collectively regulate inflammatory and inhibitory responses. Abnormal expression of TNFRSF14 is observed in approximately 40% of patients with follicular lymphoma (FL). HVEM inhibits T cell activation through its interactions with receptors on both B cells and T cells, which is crucial for maintaining immune balance and preventing excessive immune reactions.
In the pathological process of MS, TNFRSF14 may influence disease progression by modulating the interactions between immune cells and central nervous system (CNS) cells. Abnormal function of TNFRSF14 can lead to the overactivation of immune cells, triggering a misdirected attack by the immune system on the myelin sheath of the CNS, which results in an inflammatory response—an established pathological feature of MS. Furthermore, TNFRSF14 may play a role in modulating the immune microenvironment within the CNS, where abnormalities could disrupt immune tolerance mechanisms and exacerbate the development of MS .Studies have shown that the polymorphism of the TNFRSF14 gene is associated with the susceptibility to MS43. In addition, TNFRSF14 can also affect the function of T cells, thereby regulating the intensity and duration of the inflammatory response44. Proper regulation of TNFRSF14 may mitigate neurological damage resulting from excessive inflammation in MS. Furthermore, studies indicate that TNFRSF14 can enhance the survival and activity of CD4 + memory T cells45. This enhancement facilitates effective immune surveillance, protecting against pathogens while minimizing attacks on the body’s own tissues, thereby alleviating symptoms of MS. Concurrently, TNFRSF14 plays a critical role in T cell costimulatory signaling46. On one hand, it can enhance the immune response by promoting the activation, proliferation, and function of T cells; on the other hand, it can suppress excessive immune responses through co-stimulation, thereby maintaining the balance of the immune system. This bidirectional regulatory function is crucial for maintaining immune tolerance and preventing the body from generating unnecessary immune responses to self-antigens. In the central nervous system (CNS), glial cells, such as microglia and astrocytes, play a central role in the inflammatory response. TNFRSF14 influences the activation state of these glial cells through its unique signal transduction mechanism, which in turn contributes to the development of neuroinflammation and the protective processes of nerve cells .Studies have found that the continuous activation of TNFRSF14 may trigger chronic neuroinflammation, which is closely related to the disease progression of MS47. In a chronic inflammatory state, glial cells persistently release cytokines, leading to ongoing damage and degeneration of nerve cells. Furthermore, the activation of TNFRSF14 exacerbates the inflammatory response of microglia, prompting them to release a range of pro-inflammatory cytokines48. This not only exacerbates the local inflammatory response but may also promote further activation of surrounding nerve cells and glial cells, thereby accelerating the development of MS. Consequently, the relationship between TNFRSF14 and MS primarily reflects its role in immunomodulation, particularly concerning the activation of T cells and B cells, as well as the overall immune response. Nevertheless, the specific mechanisms of action and therapeutic potential of TNFRSF14 in MS require further investigation for clarification.
In this study, we observed that 7,12-dimethylbenzo[a]anthracene (DMBA) binds significantly to TNFRSF14. As a carcinogen, DMBA’s role extends beyond direct DNA damage; it also promotes tumor development by influencing cell proliferation. This process is accompanied by complex immune regulation, including an increase in regulatory T cells and modulation of both humoral and cellular immune responses. Studies have demonstrated that DMBA can elevate the number of regulatory T cells49. As the dosage of DMBA increases, the immune response diminishes, leading to Treg cell proliferation and an immunosuppressive state. Additional research has indicated that DMBA exerts inhibitory effects on both cellular and humoral immunity in mice50,51. Regarding humoral immunity, DMBA significantly reduces antibody production. In our experiments, the quantity of antibodies produced by DMBA-treated mice post-vaccination was markedly lower than that of control mice. In terms of cellular immunity, DMBA treatment resulted in diminished cytotoxic T cell function, abnormal immune cell activation, and reduced cytokine secretion, suggesting that DMBA has a direct toxic effect on immune cells. The immunosuppressive effects of DMBA intensify with increasing doses, and the observed increases in T cells, antibody production, and cytotoxic T cell function are all dose-dependent. As research deepens and the immune mechanisms affected by DMBA are further explored, novel strategies may emerge for the prevention and treatment of related diseases.
The relationship between OGA and MS
O-GlcNAcase (OGA) plays a critical role in regulating protein glycosylation modifications, primarily by catalyzing the hydrolysis of O-GlcNAc on proteins52. In the dynamic process of O-GlcNAcylation, O-GlcNAc transferase (OGT) and OGA function in concert. OGT is responsible for adding monosaccharides to proteins, while OGA removes these monosaccharides, thereby maintaining a dynamic balance of protein O-GlcNAcylation levels. This precise regulation is essential for the structural integrity, functional performance, and stability of proteins, and it plays a central role in key biological processes, including cell signal transduction, metabolic regulation, immune response, and tumor initiation and progression. Consequently, the balance of OGA and OGT activities is vital for sustaining the stability of the intracellular environment.
MS is a chronic inflammatory disease of the central nervous system that is mediated by the immune system. It is characterized by the destruction of the myelin sheath, which exposes nerve fibers and adversely affects the transmission of nerve signals, leading to a range of neurological dysfunctions. Previous studies have indicated that OGA plays a crucial role in various signaling pathways, primarily by removing glycosylation modifications that regulate numerous cellular processes. In particular, the MAPK/ERK signaling pathway is significant for cell proliferation, differentiation, and survival. OGA influences cell proliferation and differentiation through the regulation of key genes. Some research has demonstrated that differentially expressed genes targeted by OGA are associated with the MAPK/ERK signaling pathway, where gene upregulation can enhance cell proliferation and alter differentiation53. In the G-protein coupled receptor (GPCR) signaling pathway, GPCRs play a crucial role in various physiological processes as a significant mechanism for signal transduction. The activity of OGA influences the function of GPCRs by modulating their glycosylation state, which can alter the affinity and signaling capacity of these receptors. Consequently, this modulation may impact cellular responses to external stimuli54. OGA is associated with various growth factor signaling pathways, including insulin and epidermal growth factor. These pathways are crucial for cell growth and metabolism. OGA modulates the efficiency of growth factor signaling by removing O-GlcNAc modifications, thereby influencing cellular responses to growth factors. In pathways related to the extracellular matrix (ECM), the ECM serves a vital role in providing cell support and facilitating signaling. OGA regulates the interaction between cells and their microenvironment by modulating the expression of ECM-related genes. Notably, multiple ECM-related genes are identified among the differentially expressed genes targeted by OGA, which may enhance cell migration and tissue reconstruction53. OGA activity is closely linked to mitochondrial function, as mitochondria serve as the energy production factories of the cell and play a crucial role in cell signaling. Research has demonstrated that the copy number of mitochondrial DNA and the activity of mitochondrial enzymes are associated with OGA activity and the levels of OGT protein. This suggests that OGA may influence the cellular metabolic state by modulating mitochondrial function55. OGA may play a crucial role in the regulation of the cell cycle. Glycosylation modifications impact the stability and activity of cyclins. OGA functions by removing these modifications, thereby regulating cell cycle progression and influencing cell proliferation and growth53. In addition, OGA is also associated with the immune response. It may influence the secretion of cytokines and the transmission of immune signals by regulating the glycosylation status of immune cells, and thus play a role in inflammatory responses and autoimmune diseases .Studies have indicated that OGA may influence the function and signaling of nerve cells by regulating the glycosylation state of specific neural proteins56. Abnormal glycosylation can lead to structural instability of myelin-related proteins, thereby increasing the susceptibility of myelin to immune attack or dysfunction, and contributing to the pathological processes associated with MS57. OGA may influence nerve cell function and disease progression in MS by regulating the glycosylation state of neuroproteins. The potential application of OGA inhibitors in the treatment of MS has garnered significant attention. OGA is crucial for the regulation of O-GlcNAcylation; by inhibiting OGA, the levels of O-GlcNAc can be elevated, thereby modulating signaling pathways associated with inflammation and neuroprotection58,59. The inhibition of OGA can also improve the metabolic state of cells, such as increasing glucose metabolism, which is crucial for the neuroprotection and functional recovery of patients with MS60. Clinical studies have shown that OGA inhibitors perform well in terms of tolerability and safety, demonstrating their potential in the treatment of MS61. In conclusion, OGA plays a regulatory role in various signaling pathways and has significant implications for the immune system, inflammatory response, myelin regeneration, and receptor alterations. These factors not only influence the physiological state of cells but also contribute to the onset and progression of diseases. Future inhibitors targeting OGA have demonstrated considerable potential in the treatment of MS. By modulating O-GlcNAcylation, enhancing metabolic function, and exhibiting anti-inflammatory effects, these compounds may pave the way for new treatment options for MS patients.
Despite implementing a rigorous data analysis process and employing a series of the latest GWAS data, this study acknowledges several limitations. Firstly, the focus on populations of European ancestry raises concerns regarding the generalizability of the conclusions to other ethnic groups, necessitating further in-depth exploration. Variations among ethnic groups in genetic makeup and living environments may influence the broader applicability of the research findings. Secondly, during the integration of original data for the meta-analysis of differentially expressed genes in plasma proteins, the use of diverse data sources, such as microarrays and bulk RNA sequencing with varying sample sizes, may introduce biases. The differences in data collection and analysis methods can complicate the accurate identification of differentially expressed genes. Thirdly, the expression quantitative trait loci (eQTLs) vary with disease progression due to differences in cell types. The eQTLs derived from bulk RNA sequencing face significant constraints when elucidating the key molecular mechanisms associated with diseases. Specifically, the mechanisms governing plasma protein expression in vivo differ from those observed in vitro, making it inappropriate to directly extrapolate in vitro data to represent all plasma protein functions. Additionally, alterations in various cell types throughout the disease development process may further hinder the identification of critical molecular mechanisms. Lastly, a small sample size and unbalanced grouping can lead to errors in the analysis. Although high thresholds and multiple corrections have enhanced analytical accuracy, there remains a risk of overlooking genuine associations that may lack statistical significance in smaller samples.Fifthly, the subtle effects of genetic variations may diminish statistical power and elevate the likelihood of false positives. Sixthly, the pathogenic mechanisms of diseases are exceedingly complex, involving genetic factors, environmental influences, and numerous unknown variables. To address these gaps, large-scale, multi-center, and rigorously designed studies are essential. Only through such comprehensive investigations can the associations between various factors and diseases be accurately elucidated, thereby establishing a scientific foundation for effective prevention and treatment strategies.
Future studies should prioritize multi-ethnic correlation research to enhance the applicability of findings. Currently, correlation studies focused on Asian populations are progressing rapidly, and we anticipate the opportunity to conduct multi-ethnic correlation studies by gathering datasets from various ethnicities and regions to increase sample diversity. Simultaneously, we will employ meta-analysis techniques to synthesize results from different datasets, thereby enhancing the generalizability of our findings. To our knowledge, published pQTL data is available for Asian populations, and we plan to perform MR analysis of drug targets specific to these groups in the future. Additionally, in the realm of molecular docking, evaluating binding energy is critical for predicting ligand-receptor interactions; however, its application faces several limitations that hinder its accuracy and practicality in drug design and screening.In response to this limitation, future experimental studies will play a crucial role that cannot be overlooked. First, to investigate expression differences, we will utilize RT-qPCR and Western blot (WB) techniques to analyze the expression levels of the EVI5, OGA, and TNFRSF14 genes and proteins in Jurkat, Raji, C6, OLN-93, and PC12 cells. Secondly, for gene function exploration, we will employ cell transfection technology to knock down and overexpress the corresponding genes, monitoring various indicators at the gene and protein levels (qPCR, Western blot), as well as assessing cell function (CCK-8 proliferation, Annexin V-FITC/PI double staining for apoptosis), and evaluating cytokines and signaling pathways (ELISA for cytokines, Western blot for signal protein phosphorylation). Finally, regarding animal gene research, we will select adeno-associated virus (AAV) or lentiviral vectors to deliver the CRISPR-Cas12a system and target crRNA for gene editing, assessing the effects of gene knockout from multiple levels. At the molecular level, tissue sample DNA will be extracted, and qPCR and gene sequencing will be employed to verify the knockout of the target gene, while mRNA expression changes will be assessed via qPCR. At the protein level, Western blot or immunohistochemistry will be utilized to detect the expression of the target protein and evaluate its impact on protein synthesis. At the cellular level, we will analyze the phenotype, activation status, and quantity changes of oligodendrocytes through flow cytometry by isolating target tissue cells.
